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Loss of PINK1 enhances neurodegeneration in a mouse model of Parkinson's disease triggered by mitochondrial stress.

Abstract：

:Parkinson's disease (PD) shows a complex etiology, where both genetic and environmental factors contribute to initiation and advance of pathology. Mitochondrial dysfunction and mutation of genes implicated in mitochondria quality control are recognized contributors to etiopathology and progression of PD. Here we report the development and characterization of a genetic mouse model of PD with a combined etiology comprising: 1) induction of mitochondrial stress achieved through the expression of a mitochondrial matrix protein that accumulates in an unfolded state and 2) deletion of PINK1 gene. Using this model we address the role of PINK1 in mitochondrial quality control and disease progression. To induce mitochondrial stress specifically in catecholaminergic neurons we generated transgenic animals where the conditional expression of mitochondrial unfolded ornithine transcarbamylase (dOTC) is achieved under the tyrosine hydroxylase (Th) promoter. The mice were characterized in terms of survival, growth and motor behaviour. The characterization was followed by analysis of cell death induced in dopaminergic neurons and responsiveness to l-dopa. We demonstrate that accumulation of dOTC in dopaminergic neurons causes neurodegeneration and motor behaviour impairment that illustrates a parkinsonian phenotype. This associates with l-dopa responsiveness validating the model as a model of PD. The combined transgenic model where dOTC is overexpressed in PINK1 KO background presents increased neurodegeneration as compared to dOTC transgenic in wild-type background. Moreover, this combined model does not show responsiveness to l-dopa. Our in vivo data show that loss of PINK1 accelerates neurodegenerative phenotypes induced by mitochondrial stress triggered by the expression of an unfolded protein in this organelle.

journal_name

Neuropharmacology

journal_title

Neuropharmacology

authors

Moisoi N,Fedele V,Edwards J,Martins LM

doi

10.1016/j.neuropharm.2013.10.009

subject

Has Abstract

pub_date

2014-02-01 00:00:00

pages

350-7

eissn

0028-3908

issn

1873-7064

pii

S0028-3908(13)00483-8

journal_volume

77

pub_type

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